Apoptosis is one of the major mechanisms for control of cell death. It plays an important role during neuronal development and in the homeostasis of the nervous systems in adult animals. Abnormal apoptosis may cause or contribute to various neurodegenerative disorders including stroke, epilepsy, Parkinson's disease, Huntington's disease, and Alzheimer's disease. Elucidation of mechanisms that regulate neuronal apoptosis is of fundamental importance for neurobiology and may ultimately lead to the development of pharmacological interventions and clinical strategies for treatment of various neurodegenerative disorders. The overall objective of the proposal is to identify signal transduction pathways for apoptosis in neurons of the central nervous system. Recently, we discovered that three members of the mitogen- activated protein (MAP) kinase family, ERK, JNK, and p38, mediate opposing effects on apoptosis induced by withdrawal of NGF from NGF- differentiated PC-I 2 cells. NGF withdrawal led to a delayed but sustained activation of the JNK and p38 MAP kinases and inhibition of ERKs. The activation of JNK and p38 and concurrent inhibition of ERK were both critical for induction of apoptosis in these cells. While activation of the ERK signaling pathway promoted cell survival, stimulation of the JNK and p38 signaling pathways contributed to cell death. We hypothesize that the dynamic balance between growth factor- activated ERK and stress-activated JNK-p38 pathways determines whether neurons survive or undergo apoptosis. The overall objective of this proposal is to test the generaLity of this hypothesis for neurons from different parts of brain in response to several types of cellular stress. The specific aims of this proposal are to determine if JNK or p38 MAP kinases are activated, while the ERKs are inhibited during apoptosis in primary cultured neurons; determine if direct activation of JNK and/or p38 is sufficient to induce apoptosis in primary cultured neurons; determine if inhibition of JNK or p38 signaling pathways prevents apoptosis in primary cultured neurons; determine if activation of ERKs exerts neural protective effects against apoptosis in primary cultured neurons; and determine if the activation of JNK and p38 is critical for the induction of apoptosis in cultured hippocampal slices.